Suppression of covid-19 replication by covid-19 entry inhibitors

Abstract

The present invention relates to compounds, compositions, and methods, for treating viral infections. In particular, entry inhibitor compounds are disclosed for treatment of coronavirus infections, including SARS-COV-1 and SARS-COV-2 infections. The compounds bind to the interface of a SARS-COV-2 spike protein receptor binding domain (RBD) and a host cell ACE-2 receptor. The entry inhibitor compounds show antiviral activity, favorable kinetics, and temporally act at the entry of SARS-COV-2 infection. In embodiments, the compounds are used as medicaments for the inhibition of viral replication including SARS-COV-1 and/or SARS-COV-2 replication, for the treatment or prophylaxis of viral infections including SARS-COV-1 and SARS-COV-2 infections, and/or for the treatment or prophylaxis of an illness due to SARS-COV-1 and SARS-COV-2 infections.

1 . A compound having one of the following formulae: 
       
         
           
           
               
               
           
         
       
       or
 a pharmaceutically acceptable salt thereof for use in a medical therapy or a prophylactic treatment of a viral infection, 
 wherein each of R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 3  and R′ is independently hydrogen, halogen, nitro (—NO 2 ), aldehyde, carbonyl, carboxyl, hydroxyl, amine, aryl, heteroaryl, aryloxy, heteroaryloxy, —O(C 1 -C 4 )alkyl, —O(C 1 -C 4 )haloalkyl, (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkyl substituted with one or more halogen; 
 R 5  is independently hydrogen, halogen, aldehyde, carbonyl, carboxyl, hydroxyl, amine, aryl, heteroaryl, aryloxy, heteroaryloxy, (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, —O(C 1 -C 4 )alkyl, or —O(C 1 -C 4 )haloalkyl; 
 each of R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17  and R 18  is independently hydrogen, halogen, nitro (—NO 2 ), aldehyde, carbonyl, carboxyl, hydroxyl, amine, aryl, heteroaryl, aryloxy, heteroaryloxy, —O(C 1 -C 4 )alkyl, —O(C 1 -C 4 )haloalkyl, (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkyl substituted with one or more halogen, 
 Y is O, S, S(═O), S(═O) 2 , carbonyl, carboxyl, (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkyl substituted with one or more halogen; 
 Z is O, S, S(═O), S(═O) 2 , carbonyl, carboxyl, (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkyl substituted with one or more halogen; 
 Y 1  is O, S, S(═O), S(═O) 2 , nitro (—NO 2 ), aliphatic nitrile, carbonyl, carboxyl, (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkyl substituted with one or more halogen; 
 X 1  is S, O, NH, or CR a1 , X 2  is N or CR a2 , X 3  is N or CR a3 , and X 4  is a (C 1 -C 4 )alkyl, wherein each of R a1 , R a2 , and R a3  is independently hydrogen, halogen, hydroxyl, (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, aryl, heteroaryl, aryloxy, heteroaryloxy, —O(C 1 -C 4 )alkyl, or —O(C 1 -C 4 )haloalkyl; 
 L is absent or CR a4 , wherein R a4  is hydrogen, halogen, hydroxyl, (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, aryl, heteroaryl, aryloxy, heteroaryloxy, —O(C 1 -C 4 )alkyl, or —O(C 1 -C 4 )haloalkyl; and 
 M is absent, NH, or N, wherein when M is N, M and X 4  bind to form a cyclic group. 
 
     
     
         2 . The compound of  claim 1 , wherein each of R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8  and R 9  is independently hydrogen, nitro (—NO 2 ), O(C 1 -C 4 )alkyl, —O(C 1 -C 4 )haloalkyl, (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkyl substituted with one or more halogen;
 R 5  is independently hydrogen, halogen, (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, —O(C 1 -C 4 )alkyl, or —O(C 1 -C 4 )haloalkyl; 
 each of R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17  and R 18  is independently hydrogen, halogen, nitro (—NO 2 ), NH 2 , O(C 1 -C 4 )alkyl, —O(C 1 -C 4 )haloalkyl, (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkyl substituted with one or more halogen, 
 Y is O, S, S(═O), or S(═O) 2 ; 
 Z is O, S, S(═O), or S(═O) 2 ; 
 Y1 is O, S, S(═O), S(═O) 2 , nitro (—NO 2 ), or aliphatic nitrile; 
 X 1  is S, O, or CR a1 , X 2  is N or CR a2 , X 3  is N or CR a3 , and X 4  is a (C 1 -C 4 )alkyl, wherein each of R a1 , R a2 , and R a3  is independently hydrogen, halogen, (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, —O(C 1 -C 4 )alkyl, or —O(C 1 -C 4 )haloalkyl; 
 L is absent or CR a4 , wherein R a4  is hydrogen, (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, —O(C 1 -C 4 )alkyl, or —O(C 1 -C 4 )haloalkyl; and 
 M is absent, NH, or N, wherein when M is N, M and X 4  bind to form a cyclic group. 
 
     
     
         3 . (canceled) 
     
     
         4 . The compound of  claim 1 , wherein the compound of formula (I) is 
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound of  claim 1 , wherein the compound of formula (II) is 
       
         
           
           
               
               
           
         
       
     
     
         6 . The compound of  claim 1 , wherein the compound of formula (III) is 
       
         
           
           
               
               
           
         
       
     
     
         7 . A pharmaceutical composition, comprising:
 the compound of  claim 1 ; and   a pharmaceutically acceptable carrier.   
     
     
         8 . A method for preventing and/or treating a viral infection in a mammal in need thereof, comprising:
 administering to a mammal an effective amount of the pharmaceutical compound of  claim 1 , wherein the pharmaceutical compound or pharmaceutically acceptable salt thereof binds to an interface of a SARS-COV-1 or SARS-COV-2 spike protein receptor binding domain (RBD) and a host cell ACE-2 receptor.   
     
     
         9 . The method of  claim 8 , wherein the viral infection comprises infection with SARS-COV-1, SARS-COV-2, MERS-COV, NL63-COV, 229E-COV, OC43-COV, HKU1-COV, WIV1-COV, MHV, HKU9-COV, PEDV-COV, and/or SDCV. 
     
     
         10 . The method of  claim 9 , wherein the mammal is human. 
     
     
         11 . The method of  claim 10 , wherein the compound or pharmaceutical composition is administered orally, intraperitoneally, or intravenously. 
     
     
         12 . The method of  claim 11 , wherein the compound or pharmaceutical composition is administered by a non-oral route. 
     
     
         13 . The method of  claim 12 , wherein a therapeutically effective amount is an amount that blocks the replication of a SARS-COV-1 or SARS-COV-2 virus. 
     
     
         14 . The method of  claim 13 , wherein a therapeutically effective amount is an amount that prevents entry of a SARS-COV-1 or SARS-COV-2 virus mediated by a spike protein of the SARS-COV-1 or SARS-COV-2 virus into a cell of the mammal. 
     
     
         15 . The method of  claim 14 , wherein the compound of formula (II) is administered and comprises an entry inhibitor for the SARS-COV-1 or SARS-COV-2 virus. 
     
     
         16 . The method of  claim 15 , wherein an additional antiviral agent is administered in combination with the compound of formula I, II, or III. 
     
     
         17 . The method of  claim 16 , wherein the additional antiviral agent is a nucleoside analogue. 
     
     
         18 . The method of  claim 17 , wherein the nucleoside analogue is remdesivir or ribavirin. 
     
     
         19 . The method of  claim 18 , wherein the compound or pharmaceutical composition inhibits viral replication and/or prevents entry of the SARS-COV-1 or SARS-COV-2 virus mediated by the spike protein of the SARS-COV-1 or SARS-COV-2 virus into the cell at a nanomolar range. 
     
     
         20 . (canceled) 
     
     
         21 . A method of treating a SARS-COV-2 virus, comprising administering a compound to the subject, wherein the compound binds to SARS-COV-2 S-RBD/ACE2 Complex but does not bind to S-RBD alone or ACE-2 alone, wherein the compound comprises formula (IIa), or a pharmaceutically acceptable salt thereof. 
     
     
         22 . The method of  claim 2 I, wherein the compound of formula (II) is